Incidence of acquired immunodeficiency syndrome (AIDS) has markedly declined in the USA through implementation of the development of highly active antiretroviral therapy (HAART). However, the proportion of females who were newly infected by human immunodeficiency virus type 1 (HIV-1) through heterosexual contacts is rapidly increasing. Indeed, one in three new cases of HIV-1 infection in the USA now occur in females. HAART may significantly reduce but does not eliminate the risk of heterosexual transmission. HIV-1 infection is also highly compartmentalized within the body. In order to effectively prevent heterosexual HIV-1 transmission, it is important to understand; (a) Which compartment(s) are heterosexually (male-female or female-male) transmitted HIV-1 derived from? (b) How readily does HIV-1 migrate from one compartment to the others? Based on existing (albeit rather scant) data, we hypothesize; (i) that HIV-1 in the blood and the genital tracts of infected individuals form separate compartments, each of which is "well insulated but not closed" and maintains a relatively "autonomous" viral dynamics, and also (ii) that HIV-1 heterosexual transmission are mediated by cell-free (M-tropic) genital viruses. We propose to examine our hypotheses through investigation of the cell-free and the cell-associated HIV-1 populations of the blood and the male/female genital tracts. Specifically, we will address the following questions: (1) What are the genetic distances (a) within "cell-free" and "cell-associated" HIV-1 population of the blood and the genital compartments, respectively; and (b) between each of the four populations? (2) Do the viral replication dynamics of HlV-1 compartment(s) differ from one to the others? (3) Do all compartments similarly respond to antiretroviral therapy (ART)? And are the patterns of drug resistance mutations identical in all the compartments? And finally, (4) From which HIV-1 compartment(s) is a heterosexually transmitted virus derived? The proposed study will clearly elucidate which HIV-1 compartment(s) is directly associated with heterosexual transmission, and how each HIV-1 compartment responds to an antiretroviral therapy. Efficacy of HAART to reduce HIV1 sexual transmission risk may need to be evaluated for its ability to reduce the genital, rather than the plasma, HIV-1 compartments.